Blood substitutes have been sought for many years to sustain the lives of human and animal subjects in the absence of the subject's own blood. In addition, such blood substitutes have been sought for the purpose of the preservation of vital organs of organ donors after their deaths.
Recently, advances in surgical methods have permitted surgeons to carry out extremely time-consuming and complicated surgical procedures. However, such procedures frequently require that the subject's body temperature is lowered to minimize the damage to the subject's vital organs, particularly the central nervous system which, because of its high metabolic demands, requires large amounts of oxygen and glucose. The potential for carrying out such complicated surgical procedures on the organs of the central nervous system and the major blood vessels, for example are severely limited due to this physiological requirement. Lowering the temperature of the euthermic subject to a temperature well below that normally maintained by the subject reduces the metabolic rate, and hence the demands for oxygen and glucose of the central nervous system as well as other vital tissues and organs.
A number of blood substitutes have been developed in the past. These blood substitutes have been used primarily for the purpose of preservation of surgically removed organs obtained from organ donors to be later used in transplant surgery. Some of the contents of these solutions are described in table 1. From this table it is readily seen that the majority of these blood substitutes are solutions of substances that readily permeate through the vasculature of the subject's or the donor's organs and are thus generally inappropriate for use in surgery performed on a living patient. Thus, the blood substitutes of Collins et al, Kidney preservation for transplantation. Lancet 1219-1222 (1969), Collins G.M., Hypothermic kidney storage. Transplant. Proc. IX:1529 (1977), Fischer et al, Flush solution 2, a new concept for one to three day hypothermic renal storage preservation. Transplantation 39:2, 122-126 (1985), Ross et al, 72-hour canine kidney preservation without continuous perfusion. Transplantation 21:498 (1976), Sacks et al, Transplantation 19:283 (1974) and Kallerhoff et al, Effects of the preservation conditions and temperature on tissue acidification in canine kidneys. Transplantation 39:5, 485-489 (1985) all consist only of low molecular weight molecules that readily traverse the capillary bed of the subject and thus are generally incapable of maintaining proper ionic or fluid balance or plasma volume. Nonetheless, Klebanoff and Phillips, Cryobiology 6:121-125 (1969) disclosed hypothermic asanguinous perfusion of dogs with 11 of 15 subject's surviving up to 95 minutes when perfused with buffered Ringer's lactate at 7.1 to 16 degrees C. (44.6-60.4 degrees F.).
Those blood substitutes that have an impermeable substance to maintain volume use human serum albumin, a mixture of plasma proteins, as the impermeate molecule to maintain blood volume. Wall et al, Simple hypothermic preservation for transporting human livers long distances for transplantation. Transplantation, 23:210 (1977). Belzer et al, Combination perfusion-cold storage for optimum cadaver kidney function and utilization. Transplantation 39:2, 118-121, (1985).
Haff et al. Journal of Surgical Research 19:1, 13-19 (1975) describe the asanguineous hypothermic perfusion of dogs using two solutions: the first a flush solution comprised of pooled delipidated homologous plasma and electrolytes and the second comprised of pooled delipidated homologous plasma, electrolytes and additional potassium chloride at a concentration of 10 mEq/liter. Haff et al also disclose the use of a pulsatile pump oxygenator and hypothermic perfusion with the above-mentioned solutions and suggest that the procedures could be used for long distance transport of cadaver organ donors and as an alternative to hypothermic circulatory arrest for blood-free intricate surgery. Haff et al, however, failed to monitor pulmonary arterial wedge pressure during the procedure, and thus exposed the subject animals to probable damage to the alveoli of the lung.
The forgoing plasma-based blood substitutes, however, have a disadvantage unforeseen at that time they were developed. If applied to human beings they would require the processing of human blood to obtain plasma or plasma proteins. However such human blood may be contaminated with life threatening virus particles such as HTLV-1, HIV or Hepatitis A or B or nonA-nonB virus. For the forgoing reasons, non-blood based blood substitutes are clearly desirable to eliminate the danger of infection associated with human blood-based products.
Bishop et al. Evaluation of hypertonic citrate flushing solution for kidney preservation using the isolated perfused rat kidney. Transplantation 25:5, 235-239 (1978) discloses a perfusion solution that included 50 g/liter dextran 40, a concentration that differs markedly from that of the blood substitute of the present invention. In addition, the electrolyte and ion concentrations differ markedly from those disclosed for the present invention. Segall et al. Federation Proceedings 44(3):623, (1985) disclose that a Ringer's lactate-based heparinized blood substitute containing 6% dextran 40 was used to lower the body temperature of hamsters prior to the circulation of cold-protective solutions, which are not disclosed, for 1 to 1.5 hours.
Segall et al (1987) disclose that a blood substitute, which included dextrose (180 mg/dl) and 25 mM HEPES, was used to perfuse a dog to 3 degrees C. when perfusion was stopped entirely. There is no disclosure of the complete composition of the blood substitute.